Treatment of Treatment of Mild to moderate Mild to moderate

Extensive Extensive Ulcerative ColitisUlcerative Colitis

Philippe Marteau, Paris, FrancePhilippe Marteau, Paris, France

Mild to moderate Extensive UCMild to moderate Extensive UC

Oral ASA are needed as local treatments cannot cover all lesions

Recommendation : 1st line : oral 5-ASA 4 g/dObtaining endoscopic remission or frank improvement

usually takes more than 4 weeks

2nd line : if severe or resistant : consider oral steroids

Marteau P et al. Gastroenterol Clin Biol. 2004 Oct;28(10 Pt 2):955-60.

UC Consensus 2006UC Consensus 2006Treatment of Active DiseaseTreatment of Active Disease

Simon Travis, Eduard Stange, Simon Travis, Eduard Stange, Yehuda Chowers, Philippe Yehuda Chowers, Philippe MarteauMarteau

Active disease Active disease ECCO Statement: Extensive colitisECCO Statement: Extensive colitis

● Extensive ulcerative colitis of mild-moderate severity should initially be treated with mesalazine >2g/day [EL1a, RG A], combined with topical mesalazine[EL1b, RG A]

● Oral aminosalicylates alone induce remission only in a minority of patients [EL1a, RG A]….

Optimise the first line treatment of extensive UC ?

– Many symptoms originate form the distal colon

(blood in stools, tenesmus…)

– Is association of local and oral salicylates better than

oral treatment alone ?

PatientsPatients

● 116 patients

● Mild to moderate exacerbation of extensive UC (UCDAI ≥3 and ≤8)

● Exclusion criteria: ● maintenance treatt with aminosalicylates > 3 g/d● corticosteroids● immunosuppressive agents

Marteau et al. Gut 2005;54:960-5

MethodsMethods

● Double-blind, parallel-group, placebo-controlled RCT

● For 8 weeks, each patient received 4 g/d pentasa orally

● During the initial 4 weeks, each patient additionally applied daily a 100 mL enema at bedtime, either containing 1 g Pentasa or placebo

● Evaluation ● at inclusion, 4 weeks and 8 weeks ● UCDAI score (clinical signs and endoscopic evaluation of

the distal colon)

Marteau et al. Gut 2005;54:960-5

0102030405060708090

100

Rem. Imp. Rem. Imp.

week 4 week 8

%

P=0.308

P=0.0008

P=0.030

P=0.026

Pentasa orally + pentasa enema

Pentasa orally + placebo enema

Marteau et al. Gut 2005;54:960-5

Time to cessation of rectal bleeding Time to cessation of rectal bleeding Patients with frank bleeding at baselinePatients with frank bleeding at baseline

Marteau et al. Gut 2005;54:960-5

Active disease Active disease ECCO Statement: Extensive colitis (cont)ECCO Statement: Extensive colitis (cont)

Systemic corticosteroids are appropriate if symptoms of active colitis do not respond rapidly to mesalazine [EL1b, RG C],

or for patients who are already taking appropriate maintenance therapy

Active disease Active disease ECCO Statement: ECCO Statement: Oral steroidOral steroid--refractory UCrefractory UC

● Patients with persistently active, steroid-refractory disease should be treated with azathioprine / mercaptopurine [EL1b, RG B], – Although surgical options should also be discussed – intravenous steroids, – infliximab [EL1b, RG B] – or calcineurin inhibitors [EL3, RG C]

should also be considered

Active disease Active disease ECCO Statement: ECCO Statement: ThiopurineThiopurine--intolerant or intolerant or --refractory ulcerative colitisrefractory ulcerative colitis

● Infliximab [EL1b, RG B] or surgical options should be considered

● Continued medical therapy that does not achieve steroid-free remission is not recommended [EL5, RG D]

Infliximab in Ulcerative colitis ACT1 & ACT2 Rutgeerts et al. N Engl J Med 2005;353:2462-76

●● 2 RCTs 364 patients in each

● Patients with active UC (extensive 40% - 46%):– Mayo score of 6 to 12 points - Endoscopic subscore ≥2

●Either– Concurrent treatment with ≥ 1 of the following:

– Steroids, azathioprine, 6-MP, or aminosalicylates (ACT 2 only)– Failure to tolerate or respond to ≥ 1 of:

– Steroids, azathioprine, 6-MP, or aminosalicylates (ACT 2 only)

● Infliximab 5mg/kg vs 10mg/kg vs placeboAt weeks. 0,2,6 then every 8 weeks. 46 weeks

ACT 1 ACT 1 Rutgeerts et al. N Engl J Med 2005;353:2462-76

38,8

33,932

36,9

14,9 15,7

05

1015202530354045

8 Weeks 30 Weeks

Perc

ent o

f Pat

ient

s

IFX 5 mg/kgIFX 10 mg/kgPlacebo

‡

††

† 62

50,4

59

49,2

33,9

24,8

0

10

20

30

40

50

60

70

8 Weeks 30 Weeks

Perc

ent o

f Pat

ient

s

IFX 5 mg/kgIFX 10 mg/kgPlacebo

††

† †

21,7

10,1

0

5

10

15

20

25

CorticosteroidDiscontinued (Week 30)

Perc

ent o

f Pat

ient

s

IFX (combined)Placebo

†

Clinical RemissionClinical Remission EndoscopicEndoscopic RemissionRemission

Steroid discontinuationSteroid discontinuation

Infliximab (keep thiopurines) or calcineurine inhib.

AlgorithmAlgorithmOral 5-ASA (4g/d)

Oral 5-ASA (4g/d) + 5-ASA enema (or suppos?)

Oral steroids (40-60mg/d) (keep 5-ASA ?)

Tapering ... consider thiopurines (keep 5-ASA !)

Surgery

Infliximab (keep thiopurines) or calcineurine inhib.

AlgorithmAlgorithmOral 5-ASA (4g/d)

Oral 5-ASA (4g/d) + 5-ASA enema (or suppos?)

Oral steroids (40-60mg/d) (keep 5-ASA ?)

Tapering ... consider thiopurines (keep 5-ASA !)

Surgery

What happened before ?How many episodes ?Resistance to treatments ?

Severity ?Patient preferences ?Personal view on the risk/benefit

Infliximab (keep thiopurines) or calcineurine inhib.

AlgorithmAlgorithmOral 5-ASA (4g/d)

Oral 5-ASA (4g/d) + 5-ASA enema (or suppos?)

Oral steroids (40-60mg/d) (keep 5-ASA ?)

Tapering ... consider thiopurines (keep 5-ASA !)

Surgery

What happened before ?How many episodes ?Resistance to treatments ?

Severity ?Patient preferences ?Personal view on the risk/benefit

Directly ? No improvement

after 2 weeks

Infliximab (keep thiopurines) or calcineurine inhib.

AlgorithmAlgorithmOral 5-ASA (4g/d)

Oral 5-ASA (4g/d) + 5-ASA enema (or suppos?)

Oral steroids (40-60mg/d) (keep 5-ASA ?)

Tapering ... consider thiopurines (keep 5-ASA !)

Surgery

What happened before ?How many episodes ?Resistance to treatments ?

Severity ?Patient preferences ?Personal view on the risk/benefit

Directly ?

If previous failure to 5-ASA

If « rapid remissionneeded » ?

If nocturnal stools ?

No improvementafter 2 weeks

4-8 weeks

Infliximab (keep thiopurines) or calcineurine inhib.

AlgorithmAlgorithmOral 5-ASA (4g/d)

Oral 5-ASA (4g/d) + 5-ASA enema (or suppos?)

Oral steroids (40-60mg/d) (keep 5-ASA ?)

Tapering ... consider thiopurines (keep 5-ASA !)

Surgery

What happened before ?How many episodes ?Resistance to treatments ?

Severity ?Patient preferences ?Personal view on the risk/benefit

Directly ?

If previous failure to 5-ASA

If « rapid remissionneeded » ?

If nocturnal stools ?

If steroid dependencyor contra-indication

& thiopurine resistance

No improvementafter 2 weeks

4-8 weeks

4 weeks

4 - **** weeks